Austrian And UK Study Shows That SARS-CoV-2 BA.2 Variant And Its Sublineages Are Very Different Antigenically From All Other Variants

Despite calls for the BA.2 variant and its sublineages to be conferred a different name altogether so as to ensure that all therapeutics and drugs along with treatment protocols that are being studied or developed are approached from a unique and specific approach, the stupid authorities concerned are still lumping it as an Omicron variant. The same goes for the newly emerging BA.4 and BA.5 variants as well. Many so called ‘experts’ are still trying to approach these BA.2, BA.4 and BA.5 variants with knowledge and data gained since the start of the debut of the wildtype strain from Wuhan when in fact, the pathogenesis of these new variants and even how they affect the immune system and the various human cellular pathways along with their tropism have changed.


 
A new study by researchers from the Institute of Virology at the Medical University of Innsbruck-Austria and the Center for Pathogen Evolution, University of Cambridge-UK have found that the SARS-CoV-2 BA.2 variant and its sublineages are very different antigenically from all other variants.
 
Many past studies have shown that SARS-CoV-2 BA.1 Omicron is an immune escape variant and current vaccines and infection with pre-omicron variants provide limited protection against BA.1.
 
The Omicron BA.2 has in the meanwhile become the dominant variant in many countries and has replaced BA.1. As BA.2 has several mutations especially in the receptor binding and the N terminal domain compared to BA.1, the study team analyzed whether BA.2 shows further immune escape relative to BA.1.
 
The study team characterized neutralization profiles against the new BA.2 Omicron variant in plasma samples from a variety of individuals with different numbers of exposures to infection/vaccination, including samples from previously virus-naïve, BA.2 Omicron-infected individuals. To illustrate antigenic differences of the two Omicron sub-variants and pre-Omicron variants the researchers performed antigenic cartography and generated antibody landscapes.
 
The study findings showed that unvaccinated individuals after a single exposure to BA.2 had limited cross-neutralizing antibodies to pre-Omicron variants and to BA.1.
 
Consequently, the study team’s antigenic map, which included all Variants of Concern and both BA.1 and BA.2 Omicron sub-variants, showed that both Omicron sub-variants are distinct to pre-omicron variants, but that the two Omicron variant are also antigenically distinct from each other.
 
It should be noted that the antibody landscapes illustrate that cross-neutralizing antibodies against the whole antigenic space, as described in the team’s maps, are generated only after three or more exposures to antigenically close variants but also after two exposures to antigenically distinct variants.
 
The study findings describe the antigenic space inhabited by the relevant SARS-CoV-2 variants, the understanding of which will have important implications for further vaccine strain adaptations.
 
The study findings were published on a preprint server and are currently being peer reviewed.
 
The study team had earlier observed that the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Omicron BA.2 variant is immunologically different from other variants, including Omicron BA.1.
 
To date, evidence suggests that Omicron BA.1 variant is immune evasive and that vaccine- or prior infection-elicited immunity provides limited protection against infection with BA.1 variant. Nevertheless, multiple exposures to SARS-CoV-2 and those with hybrid immunity (infected and subsequently vaccinated individuals) improve neutralizing antibody (nAb) titers against BA.1.
 
A past study revealed distinct antigenic differences of pre-Omicron, BA.1, and BA.2 variants based on the sensitivity to therapeutic monoclonal antibodies.
https://www.nature.com/articles/s41591-022-01792-5
 
Certain preliminary research data indicated that both BA.1 and BA.2 variants evade nAbs to a similar extent. Notably, several of these analyses represented the vaccinated population, and the nAb profiles in SARS-CoV-2-naïve subjects after BA.2 infection are limited.
 
The study team characterized the neutralization profiles against SARS-CoV-2 Omicron BA.2-infected individuals, including those with multiple antigen exposures and infection-naïve subjects. A focus-forming neutralization assay was performed, and continuous 50% neutralizing titers were computed using non-linear regression. SARS-CoV-2 D614G, Alpha, Alpha with E384K substitution (Alpha+E484K), Beta, Gamma, Delta, Omicron BA.1 and BA.2 variants were separately grown on Vero cells overexpressing angiotensin-converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2).
 
The study team constructed antigenic maps from convalescent and doubly vaccinated groups. Antigenic variants and sera were positioned based on antibody titers in a lower-dimensional space using multidimensional scaling. Antigenic distances were computed for each serum-antigen pair from titer reduction of antigen. One unit corresponded to a two-fold dilution of neutralizing titers in the antigenic map.  Antibody landscapes were built using the adjusted P.1.1 reactivity map as the reference. The neutralizing titers are plotted above the antigen map in a third dimension in these plots.
 
It was found that in previously SARS-CoV-2-naïve subjects, nAbs were detectable following infection with Omicron BA.2 and nAbs against pre-Omicron, and BA.1 variants only occasionally exceeded the detection limit and were generally low.
 
However, in previously infected subjects, nAb titers were high against pre-Omicron variants, albeit marginally lower against the Alpha variant with E484K substitution (Alpha+E484K) and Beta variant.
 
Importantly, nAbs against Omicron BA.1 and BA.2 were observed in two and five (out of 10) individuals, respectively. Contrastingly, for those with hybrid immunity, a broader nAb response was observed against all tested variants, regardless of vaccine type (messenger ribonucleic acid [mRNA] or adenovirus-vectored vaccines). 
 
The study team next analyzed nAb titers against the SARS-CoV-2 Omicron variant for different types of samples. For instance, samples from individuals with a single exposure (non-vaccinated and infection with ancestral strain, Alpha, Beta, Delta, or Omicron [BA.1 or BA.2]), double exposure (reinfection [pre-Omicron and BA.1] or doubly vaccinated), or multiple exposures (two or three vaccinations and breakthrough infection).
 
The study team found generally augmented nAb titers against Omicron BA.2 variant in those with multiple exposures, even in BA.2-naïve subjects.
 
Interestingly, infection with either Omicron variant resulted in much higher nAb titers relative to SARS-CoV-2 wildtype or Delta-infected participants, albeit lower in those with pre-Omicron variant infection or multiple exposures.
 
It was also found that in most groups, particularly those with single/double exposure, the nAb titers were higher against Omicron BA.2 than BA.1 variant. This indicated that BA.2 variant might be antigenically situated between BA.1 and pre-Omicron variants though distinct to both.
 
Significantly, in the antigenic map, the differences between BA.1 and BA.2 were substantial compared to previous variants. D614G, Alpha, Alpha+E484K, Beta, and Gamma variants occupied a small distance on the map, with the Delta variant roughly in the same area. BA.1 variant was positioned away from other variants. Consistent with the nAb data, BA.2 variant was positioned between pre-Omicron and BA.1 variant and equidistant from Delta and BA.1.
 
Importantly, the antibody landscapes revealed that exposures to two distinct SARS-CoV-2 variants resulted in the highest reactivity against all other variants.
 
It was also found that exposure to a single variant showed the most increased reactivity against the infected variant. In pre-Omicron variant convalescent subjects, reinfection with Omicron led to a broader antibody response.
 
Also, breakthrough with Delta or either Omicron variant elicited much higher nAb titers against all SARS-CoV-2 variants. Antibody landscapes were nearly identical for BA.1 breakthrough subjects and those with BA.1 breakthrough after pre-Omicron infection, implying that a third variant exposure does not substantially augment the reactivity profile as one or two exposures do.
 
The antibody levels were higher in those with multiple exposures, and the number of exposures influenced the landscape shape.
 
The antibody reactivity was generally higher in multiple exposure groups against pre-Omicron variants but not against either Omicron sub-lineage, except in Omicron-reinfected subjects.
 
 
The study team posit three hypotheses for the augmented cross-neutralization after multiple exposures, even against non-exposed variants:
 
1) Antibody saturation against an exposed variant(s) and an increase in absolute antibody titers against unencountered variants might boost responses.
 
2) Exposure to two non-Omicron variants might boost responses against conserved epitopes common to Omicron sub-lineages.
 
3) After exposure to two different variants, the broad polyclonal response might account for Omicron neutralization.
 
The study findings revealed that the two Omicron sub-lineages were antigenically distinct from each other and previous variants.
 
Scientist and researchers involved in developing vaccines therapeutic and developing treatment protocols should pay careful attention to these study findings.
 
It should also be noted that many treatment protocols used for the past variants, are to a degree redundant in dealing with these new variants.
 
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